Role of Matrix Metalloproteinases and Therapeutic Benefits of Their Inhibition in Spinal Cord Injury

This review will focus on matrix metalloproteinases (MMPs) and their inhibitors in the context of spinal cord injury (SCI). MMPs have a specific cellular and temporal pattern of expression in the injured spinal cord. Here we consider their diverse functions in the acutely injured cord and during wound healing. Excessive activity of MMPs, and in particular gelatinase B (MMP-9), in the acutely injured cord contributes to disruption of the blood-spinal cord barrier, and the influx of leukocytes into the injured cord, as well as apoptosis. MMP-9 and MMP-2 regulate inflammation and neuropathic pain after peripheral nerve injury and may contribute to SCI-induced pain. Early pharmacologic inhibition of MMPs or the gelatinases (MMP-2 and MMP-9) results in an improvement in long-term neurological recovery and is associated with reduced glial scarring and neuropathic pain. During wound healing, gelatinase A (MMP-2) plays a critical role in limiting the formation of an inhibitory glial scar, and mice that are genetically deficient in this protease showed impaired recovery. Together, these findings illustrate complex, temporally distinct roles of MMPs in SCIs. As early gelatinase activity is detrimental, there is an emerging interest in developing gelatinase-targeted therapeutics that would be specifically tailored to the acute injured spinal cord. Thus, we focus this review on the development of selective gelatinase inhibitors

Osteolysis Affecting the Jaws in Systemic Sclerosis: Clinical and Osseous Changes Based on a Case Presentation

Objectives The aim of the current paper is to present a case of systemic sclerosis of the jaws with all the characteristics and some extensive findings. Methods Systemic sclerosis is a connective tissue condition characterized by chronic inflammatory changes, presenting with a number of symptoms. The paper aims to present a case of systemic sclerosis that had some of the characteristics of the condition unilaterally. The features were prominent and well demarcated on the panoramic radiograph. Results The panoramic radiograph of the patient showed extensive condylar head resorption almost to the level of complete flattening. Discussion The rarity of the condition and the awareness the oral radiologist must have upon presentation of similar images is the main reason for the presentation of the case. The features the case presents are both characteristic and well demarcated. Finally, the authors try to alert the clinician, who should be mindful of the fact that sclerodermatous involvement of organ systems is so pleotropic, that it may include the oral cavity, which is not always thoroughly observed, and is often left unattended by medical practitioners

Shortcut to Fmoc-protected phosphinic pseudodipeptidic blocks

(Chemical Equation Presented) A three-component condensation reaction of Fmoc-carbamate, aldehydes, and alkylphosphinic acids provides a new, direct, and efficient method for synthesizing Fmoc-protected phosphinic pseudodipeptidic blocks, directly usable for solid-phase peptide synthesis. © 2005 American Chemical Society

Matrix metalloproteinase 11 (MMP-11; stromelysin-3) and synthetic inhibitors

Matrix metalloproteinase (MMP)-11, or Stromelysin 3, is a particular member of MMP family, a group of zinc-dependent endopeptidases involved in matrix degradation and tissue remodeling. Despite intense efforts since its first characterization 15 years ago, its role and target substrates in different diseases remain largely unknown. While mice with MMP-11 deficiency display no particular phenotype, analysis of different tumorigenesis models with these mice lead to the conclusion that MMP-11 promotes tumor development. In contrast with other MMPs, MMP-11 is unable to degrade any major extracellular matrix component and unlike most of other MMPs that are secreted as inactive proenzymes and activated extracellularly, MMP-11 is secreted under active form. MMP-11 may thus play a unique role in tissue remodeling processes, including those associated with tumor progression. Although MMP-11 and other MMPs have been considered as promising targets to combat cancer, a first series of clinical trials using broad-spectrum MMP inhibitors have not led to significant therapeutic benefits. These disappointing results highlight the need for better understanding of the exact role played by each MMP during the different stages of tumor progression. Among the different strategies to fill this gap, highly specific MMP inhibitors would be of great value. This review provides an update on the selectivity profile of phosphinic MMP-11 synthetic inhibitors developed and discusses the opportunities and limitations to identify inhibitors able to fully discriminate MMP-11 from the other MMPs. © 2006 Wiley Periodicals, Inc

Active methylene phosphinic peptides: A new diversification approach

Simple, rapid, and efficient methods for P1′ diversification of phosphinic peptides have been developed, employing alkylation and Knoevenagel-type condensation reactions with active methylene phosphinic scaffolds, thus leading to a wide variety of diversified phosphinic and dehydrophosphinic peptides. © 2006 American Chemical Society

Ethical issues in withholding or withdrawal of artifical nutrition and hydration

A I M : The purpose of this study was to identify and explore the main ethical dilemmas arising for a health care team working in a clinical nutrition unit when decisions about withholding or withdrawal of artificial nutrition and hydration (ANH) of seriously ill patients have to be made. The potential factors influencing this decision-making process are also described. M A T E R I A L -M E T H O D : Fifteen health carers working in a Clinical Nutrition Unit in the United Kingdom participated in the study and qualitative research methods were used to gather data. R E S U L T S : The findings of the study illustrate that withdrawal of life-sustaining nourishment is one of the most difficult ethical dilemmas for the health care professionals. The reason for such difficulty is associated with the potential outcome of that intervention, as it brings about a patient's death. Furthermore, quality of life issues appear to influence the decision-making process. When the patient's voice is absent, the health care team takes into account the perspectives of the patient's family, in order to decide to abate life-sustaining nourishment. C O N C L U S I O N S : By exploring the health carers' attitudes on ethical issues and identifying their involvement in the decision-making process, an in-depth understanding of the process is provided. The ethical decision-making process is not an easy task. The question of whether ANH should be ethically withdrawn seems to be very complex. Health carers should take into consideration all the factors influencing the decision-making in order to contribute more effectively to facilitate the whole process

Synthesis of the phosphinic analogue of thyrotropin releasing hormone

(Chemical Equation Presented) The synthesis of the phosphinic analogue of thyrotropin releasing hormone (TRH) GlpΨ[P(O)(OH)]HisProNH2, where the scissile peptide bond of TRH has been replaced by the hydrolytically stable phosphinic bond, has been achieved by a multistep synthetic strategy, providing thus one of the most potent synthetic inhibitors of pyroglutamyl peptidase II (PPII) reported to date (170 nM). The key synthetic step, an Ugi-type condensation reaction, produced directly the suitably protected for solid-phase peptide synthesis pseudodipeptidic block FmocGlu(OMe)Ψ[P(O)(OH)] His(Tr)OH. Formation of the pyroglutamic ring was performed on solid phase, providing thus a general method for synthesizing pyroglutamyl phosphinic peptides on solid phase. Using this strategy, the phosphinic analogue of TRH has been synthesized for the first time. © 2008 American Chemical Society

Chemoselective protection of solid-phase compatible Fmoc-phosphinic building blocks

(Chemical Equation Presented) An efficient four-step synthetic strategy able to fully discriminate hydroxyphosphinyl and carboxylic groups of Fmoc-phosphinic building blocks and related analogues has been developed. The proposed method applies selective acidic removal of the phenacyl (Pac) group from the hydroxyphosphinyl functionality and protection by the 1-adamantyl (Ad) group. Reductive removal of the Pac group from the carboxylic functionality leads to Fmoc-protected phosphinic pseudodipeptidic units suitable for phosphinic peptide and library development using solid-phase peptide synthesis (SPPS). © 2006 American Chemical Society

Phosphinic peptides: Synthetic approaches and biochemical evaluation as Zn-metalloprotease inhibitors

Over the course of the last decades, phosphinic peptides have emerged as an extremely important class of Zn-metalloprotease inhibitors. The intense interest in these compounds in the field of medicinal chemistry reflects a conjunction of synthetic advances and ideal physicochemical and biochemical properties. Among the latter, the optimal tetrahedral structure of phosphinic acid moiety, which perfectly fills the requirements of transition state theory, clearly defines the mechanistical frame of their function as metalloprotease inhibitors (transition state analogues, TSA). In particular, phosphinic peptides are peptidic isosters containing a chemically stable phosphinic acid moiety which mimics the transition state tetrahedral geometry of a scissile peptide bond during enzymatic hydrolysis. Moreover, the ionic interactions of phosphinic oxyanion with catalytic Zn2+ combined with the substrate-like primary interactions of pseudopeptidic backbone with enzyme's active site, can aid the rationalization of the design and development of potent and selective Zn-protease inhibitors. In these review, we aim to resume the major achievements in this field over the last decades. In the first part, the fundamental principles of phosphinopeptidic chemistry, as these have been established by the pioneers of the field, as well as the synthesis of first-generation inhibitors are presented. In the second part, accounting as a turning point the introduction of SPPS and combinatorial practices in the field, a comprehensive description of all the recent synthetic novelties as well as the outstanding applications of phosphinopeptidic derivatives in enzymatic, biochemical and crystallographic studies is attempted. © 2004 Bentham Science Publishers Ltd

Development of potent and selective phosphinic peptide inhibitors of angiotensin-converting enzyme 2

Angiotensin-Converting enzyme 2 (ACE2), a recently identified human homologue of angiotensin-converting enzyme, is a zinc metallocarboxypeptidase which may play a unique role in cardiovascular and renal function. Here we report the discovery of potent and selective inhibitors of ACE2, which have been identified by evaluating a series of phosphinic di- and tripeptides of the general formula: Z-Xaa(PO2-CH2)YaaOH and Ac-Zaa-Xaa(PO2-CH2)YaaOH. The most potent inhibitor in this series is a tripeptide that displays a K value of 0.4 nM toward ACE2 and is 3 orders of magnitude less potent toward carboxypeptidase A. Phosphinic tripeptides exhibit high potency exclusively when the Xaa position is occupied by a pseudoproline. A model of interaction between one inhibitor of this series and ACE2 suggests that the critical role played by a proline in inhibitors, but also for substrates hydrolysis, may rely on the presence of Tyr510 in the ACE2 active site. © 2008 American Chemical Society